She will continue her investigations into endogenous nitric oxide (NO) and renal function using approaches to dissect the roles of specific NOS isoforms in control of BP and renal function, including the use of mice with targeted gene deletions and local and systemic delivery of antisense oligonucleotides in rats. She will also conduct studies with the "traditional" NOS inhibitors (L-arginine analogs), to determine whether these agents have non-selective actions, mediated via inhibition of K+-ATPase channels in renal resistance vessels. She will use in vivo and in vitro techniques to study short and long-term interactions between NO and the SNS/renal nerves, Ang II, ET and arachidonic acid products. A key feature of these proposed studies is the attempt to investigate the inter relationships between the various control systems and provide some integration. She will use both in vivo and in vitro tools to determine the renal and peripheral regulation of NOS activity as affected by age and gender. These studies will include NOS inhibitors, asymmetric dimethylarginine (ADMA), and its catabolizing enzyme, DDAH. Finally, she will evaluate the validity of the use of plasma and urinary NOX and will use Electron Spin Resonance (ESR) spectroscopy as an alternative method of determining NO production in vivo.